Solid pharmaceutical preparations include tablets, capsules, powders, granules, and so on. Among them, tablets are easily taken and can control a dose of a drug on the basis of the number thereof. Moreover, the tablets are easily handled from production to taking. Therefore, the tablets account for the largest percentage of solid preparations.
Tablets are obtained by supplying a powder as a raw material into a tablet machine and compressing the powder in the tablet machine. Such a tablet machine used is mainly a rotary tablet machine, in which powder supply, compression, and discharge are continuously performed. As the functions of tablet machines have been improved in recent years, upsizing for scaling up tablet machines and speedup for enhancing the rotation speed of tablet machines have been pursued for improving productivity.
So-called high-speed compression, in which compression is performed with a turntable rotated at a high speed, is performed at an enhanced die/punch moving speed for a shortened packing time of a powder to be compressed in a die. Therefore, there is concern about poor packability and increased tablet weight variation.
Non-Patent Document 1 discloses that the flowability of a powder subjected to compression must conventionally be as favorable as possible for obtaining tablets having small weight variation in high-speed compression, and a powder of which an angle of repose or a compressibility used as an index for the flowability is as small as possible is preferably used.
Therefore, high-speed compression is generally performed by adopting a method called wet granulation which involves granulating a raw material powder with a binder solution or water to prepare heavy granules having a small angle of repose and a small compressibility and then performing compression. Examples thereof include techniques described below.
Patent Document 1 discloses a process for producing a tablet, which involves compressing a powder containing 2 to 30% by weight of powder cellulose by wet granulation. This document discloses that the granules have an angle of repose of 35 to 42°, and granules having an angle of repose exceeding 42° cause large tablet weight variation.
Patent Document 2 discloses a technique for compressing a granulated aggregate containing 95% by weight or more of sugar alcohol. This document discloses that the granulated aggregate of sugar alcohol has an angle of repose of 40° or less, and granules having an angle of repose exceeding 40° are not preferable because of problems such as poor flowability, increased variation in packability into a die during compression, and increased tablet weight variation.
Patent Document 3 discloses a technique for granulating trehalose for compression. This document discloses that a compressibility as a standard by which flowability is determined is 40% or less, and powders having a compressibility exceeding 40% have poor flowability and cause large tablet weight variation.
Patent Document 4 discloses a technique for producing a compressed product, which involves granulating a drug, polyethylene oxide, and a granulating agent to obtain a granular powder. This document discloses that a compressibility is calculated as an index for the flowability of the granular powder and is preferably 15% or less, more preferably 10% or less.
However, the wet granulation method requires many processes such as powder mixing, granulation, drying, size selection, and compression, and energy and cost required therefore are increased. Moreover, process validation must be performed according to the number of processes. The process validation means “documented evidence with a high degree of certainty that a process will consistently produce a product meeting its predetermined specification and quality characteristics”. A larger number of processes requires a larger number of process validations and therefore requires additional labor and cost. Thus, the wet granulation method has, for the above-mentioned reasons, the disadvantage that it requires cost.
On the other hand, a direct compression method, which involves mixing a powder of an ingredient to be compressed and then directly supplying the powder into a tablet machine to produce a tablet, requires a smaller number of processes and apparatuses than those required for the wet granulation method that has often been used so far. Hence, this method requires low production cost and is known as an advantageous production process from time, energy, and process validation viewpoints.
However, in direct compression, a powder is directly supplied into a tablet machine and compressed. Therefore, it has been considered that the flowability of the powder determined using an angle of repose or a compressibility as an index directly influences tablet weight variation during compression. Therefore, the direct compression method tends to cause larger weight variation than that by the wet granulation method. Particularly, for high-speed compression performed for a short supply time of a powder into a die, there is concern about further increased weight variation.
Thus, it has generally been considered that in the direct compression method as well, a powder of which an angle of repose and a compressibility are as small as possible must be prepared for improving the flowability of the powder, as in the wet compression method. Methods for obtaining a powder for compression having a small angle of repose and a small compressibility include the use of an excipient having a small angle of repose and a small compressibility and a method which involves adding a fluidizer such as light anhydrous silicic acid (Aerosil (trade name)).
Patent Document 5 discloses an excipient for direct compression. This document discloses that the excipient for direct compression has an angle of repose of 35 to 42°, and also discloses that the excipient for direct compression having an angle of repose exceeding 42° causes a bridge in a hopper due to insufficient flowability which inhibits the discharge of a pharmaceutical composition from the hopper and also causes large tablet variation, and such an excipient is thus impossible to use in high-speed direct compression.
Patent Document 6 discloses a technique for improving the flowability of a powder, which involves adding a fluidizer such as light anhydrous silicic acid as a surface modifying base material to a medicinal ingredient and mixing them to obtain a surface-modified powder containing the medicinal ingredient. This document discloses that the surface-modified powder containing the medicinal ingredient has excellent flowability corresponding to an angle of repose of 42° or less, preferably 40° or less and therefore permits tablet production by direct compression.
As described above, a powder having a large angle of repose and a large compressibility has been judged as having poor flowability and considered to increase weight variation during high-speed direct compression. Therefore, the idea has been unexpected that such a powder is used as a powder for high-speed direct compression, and in some cases, is more suitable for the high-speed direct compression.
However, most excipients for direct compression having a small angle of repose and a small compressibility generally have low compactibility. Therefore, such an excipient, when applied to high-speed direct compression performed for a short compression time, is likely to cause problems such as insufficient hardness of tablets or compression failures such as capping. Moreover, a fluidizer has the disadvantage that it is very bulky and has very poor handleability. The addition thereof may reduce binding properties or dissolution behavior. Furthermore, even the addition of the fluidizer brings about limited improvement in flowability. The addition of the fluidizer in large amounts rather presents problems such as poor flowability of a powder.
On the other hand, means for reducing weight variation of tablets obtained by direct compression from a powder having a large angle of repose, a large compressibility, and poor flowability includes a stirring feeding method which involves placing a stirring feeder in the proximity of a supply portion into a die in the lower part of a hopper and forcibly supplying a powder into the die while compacting the powder. This method has the effect of reducing weight variation, as compared with an open feeding method in which a powder for compression is supplied into a die only by gravitation. However, it has been considered that in the stirring feeding method as well, a powder for compression of which an angle of repose and a compressibility are as small as possible must be prepared for reducing weight variation. Furthermore, in the stirring feeding method as well, higher-speed compression leads to a shorter packing time into a die. Therefore, it has been considered that a powder having a large angle of repose and a large compressibility is also unsuitable for the high-speed compression using a stirring feeder.
Thus, in direct compression, it has been known that the use of an excipient for direct compression having high compactibility is effective for enhancing the hardness of tablets or preventing compression failures such as capping or sticking. However, such an excipient for direct compression having high compactibility generally has a large angle of repose and a large compressibility. Therefore, such an excipient has been considered to be unsuitable for direct compression, particularly, high-speed direct compression and has the limited purpose of use.
For example, the excipient for direct compression is typified by crystalline cellulose. Crystalline cellulose having very high compactibility (e.g., CEOLUS (registered trademark) KG-802) is effective for the compression of low compactible drugs, and the like. However, such crystalline cellulose having high compactibility has insufficient flowability and has often been used so far such that: the crystalline cellulose is added in an amount small enough not to exert harmful influence on flowability; and the crystalline cellulose, when added in large amounts absolutely necessary for securing compactibility, is compressed at a low speed using a stirring feeder, while a fluidizer is added for improving flowability as much as possible. Only in high-speed direct compression limited to formulations having no problem of tablet compactibility, crystalline cellulose having good flowability but low compactibility (e.g., CEOLUS PH-102 or PH-302) has often been used.
Non-Patent Document 2 discloses a direct compression technique using CEOLUS KG-802. However, a compression speed in this document is merely 590 mm/s in terms of a punch moving speed and is less than a speed for a high-speed compression on a production scale. Moreover, compression is performed by adding Aerosil as a fluidizer for improving the flowability of an excipient so as to improve the flowability (angle of repose and compressibility) of a powder as much as possible.
Non-Patent Document 3 discloses a direct compression technique by a stirring feeding method also using CEOLUS KG-802. In this document, a compression speed is set to a speed in consideration of a production scale. However, compression at a much higher compression speed is desired in light of the current level of tablet machines. Moreover, this document is based on the conventional idea that the angle of repose and compressibility of a powder having poor flowability are reduced as much as possible by optimizing the amount of light anhydrous silicic acid (Aerosil) added as a fluidizer and its mixing time so as to reduce weight variation. The idea is unexpected therein that a powder suitable for high-speed direct compression using a stirring feeder is prepared. Moreover, a CV value as an index for the weight variation of tablets is 1%, which is also close to the upper limit acceptable in production. Therefore, further rise in compression speed cannot be expected.    Patent Document 1: JP-A-2001-347153    Patent Document 2: JP-A-2001-10979    Patent Document 3: JP-A-2001-213890    Patent Document 4: Pamphlet of WO 04/78212 (EP-A-1523994)    Patent Document 5: JP-A-53-127553    Patent Document 6: Pamphlet of WO 00/54752 (EP-A-1161941)    Non-Patent Document 1: The Society of Powder Technology, Japan/Division of Particulate Design and Preparations, Compression Technology of Powder, pp. 44-48    Non-Patent Document 2: Asahi Kasei Corp., Avicel report No. 57, 2002    Non-Patent Document 3: Asahi Kasei Chemicals Corp., CEOLUS report No. 1, 2003